A fundamental limitation of current drug development centers on the inability of traditional pharmaceuticals to target spatially extended protein interfaces. The majority of modern pharmaceuticals are small molecules that target enzymes or protein receptors with defined pockets. However, in general they cannot target protein-protein interactions involving large contact areas with the required specificity. Examination of complexes of proteins with other biomolecules reveals that proteins tend to interact with partners via folded sub-domains, in which the backbone possesses secondary structure. These protein sub-domains rarely remain structured once excised from the protein; much of their ability to specifically bind their intended targets is lost because they assume a manifold of shapes rather than the biologically relevant one. The α-helix is the most prevalent protein secondary structure.
α-Helices play fundamental roles in mediating protein-protein interactions. Several approaches for stabilizing peptides in helical conformations or mimicking this conformation with nonnatural oligomers have been described (Henchey et al., Curr. Opin. Chem. Biol. 12: 692-697 (2008); Home et al., Acc. Chem. Res. 41: 1399-1408 (2008); Seebach et al., J. Acc. Chem. Res. 41: 1366-1375 (2008); Patgiri et al., Acc. Chem. Res. 41: 1289-1300 (2008); Garner et al., Org. Biomol. Chem. 5: 3577-3585 (2007); Goodman et al., Nat. Chem. Biol. 3: 252-262 (2007); Chin et al., Am. Chem. Soc. 123: 2929-2930 (2001)). Examination of complexes of proteins with other biomolecules reveals that often one face of the helix featuring the i, i+4 and i+7 residues is involved in binding. Synthetic scaffolds that display protein-like functionality and reproduce the arrangement of key side chains on an α-helix would be invaluable as inhibitors of selective protein interactions.
The present invention is directed to overcoming these and other deficiencies in the art.